Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

B Acute Lymphoblastic Leukemia Clinical Trial

Official title:

A Phase 2 Study of Blinatumomab in Combination With Chemotherapy for Infants With Newly Diagnosed Acute Lymphoblastic Leukemia With Randomization of KMT2A-Rearranged Patients to Addition of Venetoclax

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06317662
• Other study ID #: NCI-2024-01994
• Secondary ID: NCI-2024-01994AA
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 31, 2024
• Est. completion date: December 21, 2027

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial tests the addition of venetoclax and/or blinatumomab to usual chemotherapy for treating infants with newly diagnosed acute lymphoblastic leukemia (ALL) with a KMT2A gene rearrangement (KMT2A-rearranged [R]) or without a KMT2A gene rearrangement (KMT2A-germline [G]). Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Blinatumomab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding venetoclax and/or blinatumomab to standard chemotherapy may be more effective at treating patients with ALL than standard chemotherapy alone, but it may also cause more side effects. This clinical trial evaluates the safety and effectiveness of adding venetoclax and/or blinatumomab to chemotherapy for the treatment of infants with KMT2A-R or KMT2A-G ALL.

Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of venetoclax in addition to a standard chemotherapy backbone and two cycles of blinatumomab in infants (aged 365 days or less at diagnosis) with newly diagnosed KMT2A-R ALL.

II. To determine in a randomized manner if the addition of venetoclax to induction chemotherapy improves end of induction minimal residual disease (MRD)-negative remission rates in infants with KMT2A-R ALL.

SECONDARY OBJECTIVES:

I. To compare event free survival (EFS) rates of infants with KMT2A-R ALL treated on arm B to those treated on arm A.

II. To compare 3-year EFS of infants with KMT2A-R ALL treated on arm A to historical controls.

III. To determine the feasibility of treating infants with KMT2A-G ALL with a Children's Oncology Group (COG) high-risk ALL chemotherapy backbone and two cycles of blinatumomab and describe their outcomes.

IV. To characterize the pharmacokinetics (PK) of venetoclax in infants.

EXPLORATORY OBJECTIVES:

I. To describe 3-year EFS of infants with KMT2A-R ALL treated on arm B. II. To describe 3-year EFS of infants with KMT2A-G ALL treated on arm C. III. To evaluate the use of high-throughput sequencing (HTS) for MRD detection in infant ALL compared to centralized flow cytometry.

IV. To characterize the PK of calaspargase pegol-mknl in infants with ALL. V. To report the incidence of CD19 negative relapse and myeloid switch relapse with protocol therapy.

VI. To evaluate the impact of venetoclax in combination with chemotherapy on T-cell subsets and function.

VII. To describe the feasibility of T-cell collection and success of T-cell manufacturing for infants with KMT2A-R ALL who receive chimeric antigen receptor (CAR) T- cell therapy after coming off protocol therapy.

VIII. To determine predictors of response and resistance to venetoclax and overall protocol therapy.

IX. To evaluate the impact of subsequent anti-cancer therapy on overall survival after coming off protocol therapy.

OUTLINE:

STEROID PREPHASE: All patients receive prednisone or prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) for 7 days prior to the start of induction therapy (on days 1-7).

Patients who are KMT2A gene rearrangement positive are assigned to the safety phase cohort. Patients who are KMT2A gene rearrangement negative are assigned to Arm C.

SAFETY PHASE COHORT:

INDUCTION: Patients receive venetoclax PO or NG once daily (QD) on days 1-7, 1-10, or 1-14, daunorubicin intravenously (IV) over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase intramuscularly (IM) or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy (methotrexate, hydrocortisone, cytarabine) intrathecally (IT) on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when absolute neutrophil counts (ANC) >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-central nervous system (CNS) extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine subcutaneously (SC) QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day

29. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

EXPANSION PHASE: After completion of Safety phase, patients who are KMT2A gene rearrangement positive are randomized to Arm A or Arm B.

ARM A:

INDUCTION: Patients receive daunorubicin IV over 1-15 minutes on days 1 and 2, cytarabine SC or IV over 15-30 minutes on days 1-14, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29, or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

ARM B: Patients are assigned to 1 of 4 cohorts.

COHORT 1:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MARMA + VENETOCLAX: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, venetoclax PO or NG QD, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

COHORT 2:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

CONSOLIDATION + VENETOCLAX: Patients receive venetoclax PO or NG QD, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

COHORT 3:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

CONSOLIDATION + VENETOCLAX: Patients receive venetoclax PO or NG QD, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MARMA + VENETOCLAX: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, venetoclax PO or NG QD, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

COHORT 4:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

ARM C:

INDUCTION: Patients receive daunorubicin IV over 1-15 minutes on days 1 and 2, cytarabine SC or IV over 15-30 minutes on days 1-14, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29, or days 1, 8, 15, 22, and 29. Patients with < 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC >= 500/uL and platelets >= 50,000/uL. Patients with >= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and methotrexate IT on days 15 and 29. Patients who are MRD > 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, methotrexate IT on days 8, 15, and 22, vincristine IV on days 15, 22, 43, and 50, and pegaspargase IM or IV over 2 hours of calaspargase pegol IV over 1-2 hours on days 15 and 43. Patients who are MRD >= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to interim maintenance 1 the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

INTERIM MAINTENANCE 1: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, mercaptopurine PO or NG on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or NG or IV on days 3-4, 17-18, 31-32, and 45-46. At the end of interim maintenance 1 (day 63), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC >= 500/uL and platelets >= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28, and methotrexate IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive methotrexate IT on days 1, 29, and 36, dexamethasone PO, NG, or IV TID on days 1-7 and 15-21, vincristine IV on days 1, 8, 15, 43, and 50, doxorubicin IV over 3-15 minutes on days 1, 8, and 15, pegaspargase IM or IV over 2 hours or calaspargase pegol IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO or NG on days 29-42, and cytarabine SC or IV over 15-30 minutes on days 29-32 and 36-39. At the end of delayed intensification (day 63), all patients proceed directly to interim maintenance 2 the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV push over 2-5 minutes of IV over 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IM or IV over 2 hours on days 2 and 22 or calaspargase pegol IV over 1-2 hours on days 2 and 23. At the end of interim maintenance 2 (day 56), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC >= 750/uL and platelets >= 75,000/uL.

MAINTENANCE: Patients receive methotrexate IT on day 1 of each cycle, vincristine IV on day 1 of each cycle, prednisone or prednisolone PO, NG, or IV BID on days 1-5 of each cycle, mercaptopurine PO or NG on days 1-84 of each cycle, and methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of interim maintenance 1 in the absence of disease progression or unacceptable toxicity.

All patients undergo bone marrow aspiration and collection of blood samples throughout the trial and undergo ECHO or MUGA at screening and end of therapy. Patients may undergo CT, MRI, FDG-PET, and/or lumbar puncture if clinically indicated.

After completion of study treatment, patients are followed up for up to 3 years.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 171
• Est. completion date: December 21, 2027
• Est. primary completion date: December 21, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 365 Days

Eligibility

Inclusion Criteria:

• All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrollment on AALL2321

• Infants (aged 365 days or less) on the date of diagnosis are eligible; infants must be > 36 weeks gestational age at the time of enrollment

• Patients must have newly diagnosed B-acute lymphoblastic leukemia (B-ALL, 2017 World Health Organization [WHO] classification), also termed B-precursor ALL, or acute leukemia of ambiguous lineage (ALAL), which includes mixed phenotype acute leukemia. For patients with ALAL, the immunophenotype of the leukemia must comprise at least 50% B lineage

• Diagnostic immunophenotype: Leukemia cells must express CD19

Exclusion Criteria:

• Patients with Down Syndrome

• Patients with secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy

• Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of infant ALL or for any cancer diagnosis prior to the initiation of protocol therapy, with the exception of:

• Steroid pretreatment:

• PredniSONE, prednisoLONE, or methylPREDNISolone for = 72 hours (3 days) in the 7 days prior to enrollment. The dose of predniSONE, prednisoLONE or methylPREDNISolone does not affect eligibility

• Inhaled and topical steroids are not considered pretreatment

• Note: Pretreatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone used during or within 6 hours prior to or after sedation to prevent or treat airway edema. However, prior exposure to ANY steroids that occurred > 28 days before enrollment does not affect eligibility

• Intrathecal cytarabine or methotrexate:

• An intrathecal dose of cytarabine or methotrexate in the 7 days prior to enrollment does not affect eligibility

• Note: The preference is to defer the diagnostic lumbar puncture with intrathecal chemotherapy to day 1 of induction to allow for cytoreduction of circulating blasts and decrease the potential for central nervous system (CNS) contamination due to a traumatic tap. If done prior to day 1 of induction, these results will be used to determine CNS status

• Hydroxyurea:

• Pretreatment with = 72 hours (3 days) of hydroxyurea in the 7 days prior to enrollment does not affect eligibility

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA) and National Cancer Institute (NCI) requirements for human studies must be met

Related Conditions & MeSH terms

• Acute Leukemia of Ambiguous Lineage
• B Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Asparaginase Erwinia chrysanthemi
Given recombinant crisantaspase IM or crisantaspase IM or IV

Procedure:
• Biospecimen Collection
Undergo collection of blood samples

Biological:
• Blinatumomab
Given IV

Procedure:
• Bone Marrow Aspiration
Undergo bone marrow aspiration

Drug:
• Calaspargase Pegol
Given IV

Procedure:
• Computed Tomography
Undergo CT

Drug:
• Cyclophosphamide
Given IV
• Cytarabine
Given IT or IV
• Daunorubicin
Given IV
• Dexamethasone
Given PO or NG or IV
• Doxorubicin
Given IV

Procedure:
• Echocardiography
Undergo ECHO
• FDG-Positron Emission Tomography
Undergo FDG-PET

Drug:
• Leucovorin
Given PO or NG or IV

Procedure:
• Lumbar Puncture
Undergo lumbar puncture
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Mercaptopurine
Given PO or NG
• Methotrexate
Given IT or IV or PO or NG

Procedure:
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Pegaspargase
Given IV or IM
• Prednisolone
Given PO or NG
• Prednisone
Given PO or NG
• Therapeutic Hydrocortisone
Given IT
• Thioguanine
Given PO or NG
• Venetoclax
Given PO or NG
• Vincristine
Given IV

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	3-year EFS of infants with KMT2A-R ALL treated on Arm B	Summary statistics will be calculated. When appropriate, comparisons of the endpoints will be conducted between patients who achieved MRD-negative remission vs those who did not, between arms, or between patients with different baseline characteristics. Analyses will be descriptive and exploratory. Arm B will be compared to Arm A as described above and to historical 3-year EFS. Comparison will be based on a one-sample test of proportion with one-sided Type I error of 0.15.	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years
Other	3-year EFS of infants with KMT2A-G ALL treated on Arm C	Summary statistics will be calculated. When appropriate, comparisons of the endpoints will be conducted between patients who achieved MRD-negative remission vs those who did not, between arms, or between patients with different baseline characteristics. Analyses will be descriptive and exploratory. The 3-year EFS rate from date of enrollment of KMT2A-G patients in Arm C will be estimated with the Kaplan-Meier method.	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years
Other	Use of high-throughput sequencing (HTS) for MRD detection in infant ALL compared to centralized flow cytometry	Pre-treatment HTS clonality and HTS MRD tracking results will be collected and compared to the required centralized flow cytometry-based MRD data to evaluate the feasibility and prognostic utility of HTS MRD evaluation in the infant ALL population.	Up to 3 years
Other	PK of calaspargase pegol in infants with ALL	PK of calaspargase pegol will be analyzed by monitoring asparaginase activity levels. Once a PK model is developed for calaspargase pegol, standard regression analysis will be used to describe the relationship between drug exposure and asparaginase activity. Additionally, asparaginase-associated toxicities will be described for the entire study population and correlated with activity levels when possible. The result of this analysis will be an estimation of potential optimal exposure expected to yield the maximum efficacy while limiting toxicity. These analyses will be exploratory and descriptive.	At completion of the trial, up to 3 years
Other	Incidence of CD19-negative relapse and myeloid switch relapse with protocol therapy	For patients who experience relapse, will collect information regarding the immunophenotype of the leukemic blasts at time of relapse. Will report on the rate of CD19 negative relapse as well as myeloid switch relapse for all patients enrolled on study. This analysis will be exploratory and descriptive.	At the time of relapse, up to 3 years
Other	Impact of venetoclax in combination with chemotherapy on T-cell subsets and function	BCL-2 inhibition is reported to alter T-cell subsets, including increased activation, enhanced cytotoxicity against leukemia cells and heightened resistance to cell death. Peripheral blood and bone marrow samples will be collected prior to and following the first course of venetoclax to evaluate effects on T-cell subsets and function following venetoclax exposure.	Prior to and following the first course of venetoclax
Other	Feasibility of T-cell collection and success of T-cell manufacturing for infants with KMT2A-R ALL who receive chimeric antigen receptor T-cell therapy	For patients that undergo T-cell collection, will collect data regarding the feasibility of T-cell collection in the context of protocol therapy. Additionally, for patients who proceed with CAR T-cell therapy after coming off protocol therapy, will collect data regarding the success of T-cell manufacturing, infusion and response to therapy in this young population, as the success of this subsequent therapy may be heavily impacted by the effect of protocol therapy on T-cell function. These analyses will be exploratory and descriptive.	After coming off protocol therapy
Other	Predictors of response and resistance to venetoclax and overall protocol therapy	Will study the inter- and intra- patient variability in the expression of apoptotic proteins (e.g., BCL-2, MCL-1, BCL-XL) and apoptotic priming at diagnosis and identify changes that occur during induction therapy in relationship to venetoclax exposure. Will then determine whether the state of BCL-2 specific apoptotic priming correlates with outcome. Will also integrate genomic and molecular features (such as developmental state, signaling, epigenomic, transcriptomic, proteomic and metabolomic states) before and after venetoclax exposure, for those assays where this type of analysis is feasible, to determine biomarkers of response and resistance to therapy for infants with ALL.	Before and after venetoclax exposure, up to 3 years
Other	Impact of subsequent anti-cancer therapy on overall survival	For all patients who remain in study follow-up after coming off protocol therapy, data will be collected regarding subsequent cancer directed therapies received as well as relapse and survival status in order to evaluate the impact of subsequent cancer directed therapy on the overall survival of patients enrolled on this study. These analyses will be exploratory and descriptive.	After coming off protocol therapy
Primary	Incidence of dose-limiting toxicities (DLTs) (safety phase)		For the duration of the induction + venetoclax cycle
Primary	Incidence of DLTs (expansion phase)	For the expansion phase, DLTs of Arm B will be assessed and monitored for the cycles that contain venetoclax (induction, consolidation, and MARMA cycles of Arm B).	During the induction, consolidation, and MARMA cycles
Primary	Minimal residual disease (MRD)-negative remission rate	The end of induction MRD-negative remission rate will be compared between Arm A and Arm B. MRD negativity is defined as achievement of complete remission and MRD < 0.01% by flow cytometry. The MRD-negative remission rate at the end of induction between Arm A and Arm B will be compared using a one-sided Z test of proportions with Type I error of 0.15.	At the end of induction
Secondary	Event free survival (EFS) rates of infants with KMT2A-R acute lymphoblastic leukemia (ALL)	The EFS rates from date of randomization of Arm B will be compared to Arm A. Comparison of EFS rates between Arm A and Arm B will be based on a one-sided logrank test with Type I error of 0.15.	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years
Secondary	3-year EFS of infants with KMT2A-R ALL	For Arm A, the 3-year EFS rate (representing a plateau rate based on the shape of EFS curves of historical data in this patient population) from the date of randomization will be compared to the stable historical 3-year EFS rate of 35% observed in AALL0631 and other international trials.	From date of randomization to treatment failure, first documented relapse following achievement of remission-1, occurrence of a second or secondary malignant neoplasm, or death, assessed up to 3 years
Secondary	Proportion of KMT2A-G patients in Arm C who are able to receive all treatment cycles before maintenance	The feasibility of treating of KMT2A-G patients with a high-risk ALL backbone and two cycles of blinatumomab (Arm C) will be assessed. Arm C treatment will be considered feasible for KMT2A-G patients if the proportion of KMT2A-G patients in Arm C who are able to receive all treatment cycles before maintenance (i.e., up to interim maintenance 2) is more than 76.8%. The proportion of patients receiving all cycles before Maintenance will be compared to 76.8% with a one-sample exact test of proportion with Type I error of 0.15.	Up to interim maintenance 2
Secondary	Pharmacokinetics (PK) of venetoclax in infants	PK samples will be collected from patients enrolled in the safety phase of the study as well as from patients randomized to Arm B in the expansion phase who consent to participate, to determine the major secondary objective of characterizing the PK of venetoclax in infants. PK samples will be evaluated in batches and standard nonlinear mixed effect modeling will be used for model building and refinement of time-concentration data. After model refinement, a non-parametric bootstrap analysis will be performed reporting the 95% confidence intervals for each PK parameter.	On days 7, 10, and 14 of induction